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BRONCHIOLAR CARCINOMA OF THE LUNG
BRONCHIOLAR CARCINOMA OF THE L U N G Review of 39 Patients Thomas H. Hewlett,
Colonel, MC, US Army, Alphonse
C. Gomez,
Major,
MC, US Army, Elmore M. Aronstam, Colonel, MC, US Army, and Arthur Steer, Colonel, MC, US Army, Denver,
Colo.
B
RONCHIOLAK carcinoma was initially described in the necropsy findings of a single case reported by Malassez14 in 1876. This observer was impressed by the fact that the major bronchi were free of tumor. Storey 23 credits Skorpil with the first report of bronchiolar carcinoma in a living patient; the tumor produced an undiagnosed shadow in an upper lobe resected in 1936. Since that time bronchiolar'carcinoma has been recognized with increasing frequency, and clinical experience with this tumor has reached a level of significance. It seems apropos, therefore, to question several of the dicta regarding bronchiolar car cinoma, which were derived solely from autopsy studies. Our experience, along with that of other observers, does not confirm a multicentricity of origin of bronchiolar carcinoma, and, further, we doubt that this tumor carries the same dismal prognosis as the more common pulmonary malignancies. Several points seem to merit consideration: review of the concepts of origin of bronchiolar carcinoma, the pathologic criteria essential for diagnosis, the relationship of this tumor to previous pulmonary disease, and, finally, examination of a documented clinical experience. THE ORIGIN OF BRONCHIOLAR CARCINOMA
The alveolar lining of the fetal lung disappears shortly after birth and this change is presumed to be functional, facilitating a more rapid interchange of gases between blood and alveolar air. The normal adult lung contains alveoli lined primarily by naked capillaries with only an occasional epithelial cell ap pearing in niches between the capillaries. There are certain pathologic circum stances under which the alveoli may become lined with epithelium; in each in stance the interalveolar septae develop a marked thickening. Such septal thick ening produces a relative immobilization of tissue, the number of capillaries is reduced and remaining capillaries are consequently displaced from the interface Prom the Thoracic Surgical Service and Department of Pathology, Fitzsimons General Hospital, Denver, Colo. Received for publication May 4, 1964. 614
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surface of the alveoli, and gaseous exchange within this altered area becomes unlikely. Such alveolar epithelization is evident in the chronic passive con gestion associated with aortic or mitral valve lesions, in chronic interstitial pneumonia, and in lipoid pneumonia. Diffuse epithelial hyperplasia along the alveolar septae can occur in man; in such instances the septae appear thickened as a result of simple piling of epithelial cell layers. Any chronic inflammatory process which initiates septal thickening by leukocytic infiltration may in turn be followed by fibrosis as the acute process subsides. Two experimental facts are of interest in regard to alveolar epithelization. Simonds and Curtis 20 noted marked alveolar epithelization about necrotic areas in the lungs following the intravenous injection of tar in heavy petrolatum into rabbits. Grady and Stewart 7 induced pulmonary tumors in strain A mice by the injection of 1:2::5:6 dibenzanthrene or methylcholanthrene; such tumors appeared after 5 weeks as a layer of cells lining alveoli. Thus, in the experi mental animal, alveolar epithelization can be produced with either benign or malignant characteristics. Two basic theories exist regarding the origin of the epithelial cells which line the alveoli in bronchiolar carcinoma. Ikeda, 11 Bell,3 and Delarue and Graham 5 were of the belief that the epithelial cells of bronchiolar carcinoma took their origin from normal alveolar epithelium. Acceptance of this theory is predicated on the belief that a normal alveolar epithelium exists in the human lung. Herbut's studies 10 have indicated that all primary carcinomas of the lung arise from the basal cells of the bronchial tree, and that either cuboidal or columnar cell types will spread along alveolar septae. Smith and Gault, 21 Storey, 23 and Liebow13 all believe that the cells which come to line the alveoli in bronchiolar carcinoma arise directly from the terminal bronchioles. In the light of accumulating clinical experience the latter theory appears more reason able. It is apparent that the early pathologic studies of bronchiolar carcinoma were carried out in patients who died with extensive pulmonary disease, and it was logical that the possibility of multicentric origin of such a tumor might be emphasized. The tumor is now recognized clinically, detected by cytologic study of sputum, and histologic study of resected specimens. Documentation of patient survivals over a period of years following treatment makes any multicentricity of origin unlikely. No doubt the enigmatic factor of host resistance is of great importance in determining whether or not a patient survives for a long period of time or develops a diffuse spread early in the course of the disease. The tumor exhibits a tendency to desquamate into alveolar spaces, thus bronchial embolization appears a likely mechanism of spread to either adjacent sites or the contralateral lung. Hawkins and associates,9 in a study of 12 Fitzsimons General Hospital pa tients treated by resection, found a total observation period of 79 years with tumor recurrence in only 2 of the patients. Storey's 23 statistical analysis of 205 cases from the files of the Armed Forces Institute of Pathology appears to sub stantiate a unicentric origin for bronchiolar carcinoma. Significant long-term
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survival rates as herein reported associated with lobectomy would not be pos sible in patients with tumors of multicentric origin. T H E PATHOLOGIC CRITERIA OF BRONCHIOLAR CARCINOMA
Gross.—Bronchiolar carcinoma may appear either as a discrete peripheral nodule of varied size or as a segmental or lobar consolidation resembling a localized pneumonic process in the state of gray hepatization. The nodular lesion may be well demarcated from the adjacent lung tissue or it may appear in an area of gross cicatrization. These nodules are soft to palpation in contradistinction to the rocklike hardness noted in association with other more common pulmonary malignancies. In those instances where the tumor involves an anatomic unit of the lung, the segment or lobe retains its normal contour in a consolidated state, the pleural surface is smooth, and lobular markings are prominent. The cut surface appears yellowish-brown in color. Necrosis and cavitation are rare, but mucus is frequently evident on the cut surface. Characteristically the larger bronchi do not reveal evidence of primary tumor; in the advanced pneumonic pattern there may be evidence of tumor extension along the course of major bronchi. Microscopic.—Typically bronchiolar carcinoma resembles adenocarcinoma, either bronchogenic or metastatic. It seems likely that many bronchiolar car cinomas have been mistakenly classified as adenocarcinomas without further study. Usually the initial pathologic report will suggest the possibility of the pulmonary lesion representing a metastasis from elsewhere in the body. Overholt's 17 re-evaluation of mucinous adenocarcinomas of the lung suggests that many bronchiolar carcinomas have been misclassified. The classic pattern is one of tall columnar cells growing along alveolar walls without disruption of the alveolar pattern. Such cells can be noted to arise in the peripheral bronchioles less than 0.1 cm. in diameter (Fig. 1). These tall columnar cells contain a finely granular cytoplasm with a vesicular nucleus located in the basal portion of the cell. Such cells may occur in a single layer or in multiple layers which give a sheetlike appearance. Cilia are uncommon (Fig. 2). It must be emphasized that the basic cell type—cuboidal, squamous, or anaplastic—may be poorly differentiated; in such cases an increased incidence of mitotic figures is noted (Fig. 3). Thickening of the alveolar septae will be noted as one proceeds from the margin toward the center of the tumor. The alveolar septae encroach on the alveolar space and fuse, producing an adenomatous pattern (Fig. 4). Papillary formation is frequent within alveolar spaces, and tumor cells may be noted lying free in alveolar spaces. Such desquamation accounts for positive bronchial washings in some patients and offers a possible source for bronchial embolization as a mechanism of tumor spread. A scirrhous, papillary, or adenomatous pattern of growth is often seen where bronchiolar carcinoma arises in an area of previous parenchymal inflammation (Fig. 5).
Vol. 48, No. 4 October, 1964
BEONCHIOLAR CARCINOMA OF LUNG
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ft •?■"* ■ <& '.. *• ^
:,
-iy
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V*
■
Fig. 1.—Bronchiolar carcinoma invading the mucosa of a medium-sized bronchus. Fig. 2.—Bronchiolar carcinoma. Cells growing on alveolar septae, alveoli distended with mucus.
The malignant cells may appear in lymphatics and blood vessels; the inci dence of these findings is not as frequent as is usually associated with the more common type of pulmonary malignancy. Marked lymphatic spread is associated with advanced disease and indicates a poor prognosis (Pig. 6). A varied cellular pattern may appear in bronchiolar carcinoma. Major bronchi are not invaded, although malignant cells may spread along their course. The tumor may remain localized to a single area for a long period. Its predilection for spread is intrapulmonary rather than via lymphatic channels.
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Direct extension to adjacent tissues is rare except in advanced terminal stages B W a t i a n of other possible sources of carcinoma is essential in estabUshlng the diagnosis of bronchiolar carcinoma. The histologie evidence of pre-existing chronic pulmonary inflammation is noted within the tumor site in more tnan 50 per cent of cases here reported. No correlation can be demonstrated between the histologie appearance of the tumor and the patient's survival.
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Fig. 5.- -Bronchiolar carcinoma arising in old cicatrix. Pig. 6.- -Perivascular lymphatic distribution of bronchiolar carcinoma. RELATIONSHIP TO PREVIOUS PULMONARY DISEASE
Bronchial obstruction is relatively frequent in association with squamous cell and anaplastic bronchogenic carcinoma; however, bronchial obstruction per se is rarely noted in association with bronchiolar carcinoma. Thus it cannot be assumed that the well-established parenchymal fibrosis frequently associated with bronchiolar carcinoma is the result of a pneumonitis secondary to bronchial obstruction. Beaver and colleagues,2 in a study of 121 cases of bronchiolar car-
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cinoma, found a positive history of previous pulmonary disease in 62 per cent. In the same study there was microscopic evidence of old inflammatory changes in 84 per cent of specimens. Spain 22 has reported the cases of 12 patients in whom the association of bronchiolar carcinoma with diffuse or focal fibrosis was marked. Auerbach 1 has observed that necropsy studies suggest that the general usage of antibacterial agents in the treatment of acute pulmonary inflammation contributes to a rising incidence of organization of pulmonary exudates. Conse quently small areas of parenchymal fibrosis appear as the sequelae of viral pneumonias. The frequent reporting of a relationship between bronchiolar car cinoma and interstitial inflammation or fibrosis cannot be ignored. Cuboidal epi thelial metaplasia occurs in a variety of pulmonary diseases as mentioned; such changes may result from a decreased respiratory function secondary to in flammatory thickening of the septae. Beaver 2 and Spain 22 have postulated that fibrosis and hyperplasia may alter the epithelium to render it more susceptible to specific carcinogens. The bronchiolar epithelial metaplasia secondary to fibrosing pneumonitis may well represent a precursor to bronchiolar carcinoma, with some degree of local hypoxia serving to trigger malignant changes in atypical epithelium. The pulmonary insult which precedes bronchiolar car cinoma need not be one pronounced in severity. It may range from repeated mild susceptibility to upper respiratory infection through the gamut of viral pneumonitis, pneumococcal pneumonia, and advanced tuberculosis. There ap pears to be good correlation between history and histologic findings of old pul monary inflammation. Random survey of pathologic reports from several hos pitals reveals fibrosis to be mentioned more frequently in relation to bronchiolar carcinoma than with the more common pulmonary malignancies. Our experi ence of significant history in 52 per cent, with positive histologic findings of previous pulmonary disease in 47 per cent, indicates that the relationship of bronchiolar carcinoma to parenchymal scarring is greater than could be at tributed to mere coincidence. CLINICAL
EXPERIENCE
Thirty-nine cases of bronchiolar carcinoma from five Army General hos pitals* have been studied. There appears to be no racial or sexual predilection for bronchiolar carcinoma. There were 24 males and 15 females in the group. Twenty-nine (74 per cent) were in the so-called cancer age group. Twenty-one (53 per cent) patients were hospitalized because of respiratory symptoms, and 18 (47 per cent) were hospitalized because of chance radiographic findings. History revealed 55 per cent to be smokers; of those with symptoms most ad mitted to chronicity with occasional periods of acute exacerbation. There is no specific symptom pattern which might be considered characteristic of bronchiolar carcinoma. Approximately 50 per cent admitted to a chronic cough of several years' duration, 9 patients presented with signs and symptoms of advanced pulmonary disease. A large volume of frothy sputum was not noted in any patient; mild hemoptysis occurred in only 5 patients. * F i t z s i m o n s , B r o o k e , W a l t e r Reed, L e t t e r m a n , a n d T r i p l e r h o s p i t a l s .
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"_,J-
Tlie physical findings were dependent upon the extent of the pulmonary pathologic condition and, being nonspecific, do not merit discussion. The roentgenographic findings associated with bronchiolar carcinoma are as protean as those attributable to pulmonary tuberculosis. A small peripheral opacity with either discrete or indefinite borders may represent a bronchiolar carcinoma. In 4 of the patients studied, a small isolated area of cavitation was evident on the routine posteroanterior films. Unilateral pleural effusion was the initial finding in 5 patients. The bilateral parenchymal infiltration or nodular pattern may simulate tuberculosis. Segmental or lobar pneumonic consolidation may lead to a tentative diagnosis of pneumonia or sequestration. The roent genographic findings recorded in the patients herein reported fall in the fol lowing categories: localized parenchymal infiltration, 47 per cent; solitary pul monary opacities, 27 per cent; bilateral parenchymal infiltrate or nodular dis ease, 16 per cent; and isolated cavitation, 10 per cent. In 5 patients the lesion was evident on roentgenograms for over one year; in 6 patients the lesion was observed for over 2 years; in one instance the lesion is documented on films over an 8-year period. Hawkins and associates,9 in a review of these several patients, noted some degree of enlargement of the lesion to be apparent in each progressive set of films. Such inadvertent roentgeno graphic documentation of a solitary pulmonary lesion affords the most accurate information in regard to the duration of disease and would tend to further discredit any theory of multicentric origin of bronchiolar carcinoma. TREATMENT AND PROGNOSIS
The classical report dealing with bronchiolar carcinoma is Storey's 23 sta tistical analysis of 205 cases which appeared in 1953. This study does much to clarify certain erroneous concepts which were established on the basis of necropsy examinations. Clinical patterns and radiographic variation were clearly presented. An attitude of hope is implied but the figures did not actually clarify the prognosis in patients treated for bronchiolar carcinoma. One hundred and fifty-five patients in the series underwent treatment; of these, 49, or 31.6 per cent, had thoracotomy, 10.2 per cent survived for 5 years after resection, while another 6.1 per cent were alive 3 years after resection. Both Overholt18 and Ochsner16 have stated that the survival rate in bronchogenic carcinoma appears to be well established within 2 years following therapy. Analysis of 39 cases of bronchiolar carcinoma treated in five U. S. Army General Hospitals has been carried out. Eleven patients (28 per cent) were not suitable for resection because of advanced disease. Diagnosis in this group was established by scalene node biopsy in 3, lung biopsy in 2, bronchial washings in 1, pleural fluid cell block in 1, and autopsy in 4. Symptomatic treatment com bined with irradiation did not delay the rapidly fatal course of the disease in these patients. Thirty patients (76 per cent) underwent exploratory thoracotomy. Of this group, 28 (81 per cent) were treated by resection, the following operations being utilized: 18 lobectomies, 5 segmentectomies, and 5 pneumonectomies.
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Lobectomy was the operation of choice except where the tumor appeared to cross an interlobar fissure. The operative mortality was 6.6 per cent. The 2 patients who died in the early postoperative period were subjected to resection despite obvious pleural spread of the disease. Thus 26 patients (92 per cent) survived over 1 year after resection. Twenty-three patients (82 per cent) have survived over 2 years (Table I ) . TABLE I. SURVIVAL : 26 PATIENTS—BRONCHIOLAR CARCINOMA TREATED BY EESECTION SURVIVAL (YR.)
NO. OF PATIENTS
1 +2 +3 +4 +5
3 5 4 5 _9_ 26
DEAD
-(2) -(3) 5
Twenty-three patients (82 per cent) of those treated by resection survived beyond the 2 year period which has been designated as that point which should predict longer survival in patients undergoing resection for bronchogenic car cinoma. Fitzpatrick 6 has recently reported a 2.5 year survival rate of 30 per cent in patients undergoing resection for bronchiolar carcinoma. Continued follow-up of our patients who survived beyond 2 years reveals that recurrence of the malignancy resulted in the death of 2 patients 3^2 years after resection; another 2 patients died of metastatic disease 6 years after resection. Thus the malignancy accounted for the eventual death of 17 per cent of those surviving beyond 2 years and suggests that a 2 year postoperative survival, clinically free of disease, does not necessarily indicate a cure. However, on the positive side of the ledger, 3 patients (13 per cent) of those who survived the 2 year period are still alive and well 10 years after resection. Tabulating figures from other published experiences along with those de rived from this study, one gains the impression that the results obtained from resection of bronchiolar carcinomas of the lung are definitely better than those associated with resection as treatment in the broad spectrum of bronchogenic malignancies (Table I I ) . TABLE NO. OP PATIENTS
AUTHOR
EXPLORED
Bronchiolar "Watsonz* Fitzpatricke Bellas U. 8. Army Barrett^
1951 1961 1961 1963 1963
33 33 21 39 31
BurforcL*
1958
1,008
II
(%)
Carcinoma 48.0 60.6 76.0 74.0
Bronchogenic Carcinoma 60.0
RESECTED
SURVIVALS
(%)
(%)
2+YR.
5 YR.
87 65 57 93 64.5
43 30 25 82
33.0
35
38
8.3 32.0 40 22.0
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Burford's report dealing with the broad spectrum. of bronchogenic car cinoma noted that 5 per cent of the patients who survived 5 years were treated for bronchiolar carcinoma. This would suggest that survival in patients with bronchiolar carcinoma exceeds that associated with other bronchogenic car cinomas. SUMMARY
Numerous clinical reports have now documented the bizarre histologic pat terns of bronchiolar carcinoma and its relationship to old pulmonary fibrosis. The radiographic patterns associated with this particular malignancy are as varied as those encountered in pulmonary tuberculosis. A high rate of resectability, even after several years of radiographic observation, suggests that this tumor tends to be localized and slow in growth. Relatively long survivals fol lowing lobectomy and long periods of x-ray observation of a questionable pul monary shadow which is eventually proved to be bronchiolar carcinoma serve as proof of the unieentricity of origin of the tumor. The inadvertent radiographic recording of the presence of these tumors over a period of years in the same patient confirms the tendency of this malignancy to remain localized for a long period. Considering the continued dismal prognosis associated with the broad spec trum of bronchogenic carcinoma, the continued reporting of experiences with bronchiolar carcinoma seems justified. This experience appears to lend credence to the rationale of an extremely aggressive surgical approach in the management of the undiagnosed pulmonary nodule or infiltrate.
REFERENCES 1. Auerbaoh, 8. H., Mims, O. M., and Goodpasture, E . W . : Pulmonary Fibrosis Secondary to Pneumonia, Am. J . Path. 28: 69, 1952. 2. Beaver, O. L., and Shapiro, J . L . : A Consideration of Chronic Pulmonary Parenchymal Inflammation and Alveolar Cell Carcinoma With Regard to a Possible Etiologie Relationship, Am. J . Med. 2 1 : 879, 1956. 3. Bell, E . T . : Hyperplasia of the Pulmonary Alveolar Epithelium in Disease, Am. J . P a t h . 19: 901, 1943. 4. Burford, T. H., Center, S., Ferguson, T. B., and Spjut, H . J . : Results in the Treatment of Bronchogenic Carcinoma, J . THORACIC SURG. 36: 316, 1958.
5. Delarue, N . C , and Graham, E . A . : Alveolar Cell Carcinoma of t h e Lung (Pulmonary Adenomatosis, Jaagsiekte?) : A Multicentric Tumor of Epithelial Origin, J . THORACIC SURG. 18: 237, 1949.
6. Fitzpatrick, H . F . , Miller, R. E., Edgar, M. S., J r . , and Begg, C. F . : Bronchiolar Car cinoma of t h e Lung, J . THORACIC & CARDIOVAS. SURG. 4 2 : 310, 1961.
7. Grady, H . G., a n d Stewart, H . L . : The Histogenesis of Induced Pulmonary Tumors in Strain A Mice, Am. J . Path. 16: 417, 1940. 8. Geever, E . F . , Neubuerger, K. T., and Davis, C. L . : The Pulmonary Alveolar Lining Under Various Pathologic Conditions in Man and Animals, Am. J . P a t h . 19: 913, 1943. 9. Hawkins, J . A., Hansen, J . E., and Howbert, J . : A Clinical Study of Bronchiolar Car cinoma: A Clue t o Unieentricity or Multicentrieity, Tr. of the 21st Research Con ference on Pulmonary Diseases, VA-Armed Forces, 1962, p . 143. 10. Herbut, P . A . : Bronchiolar Origin of "Alveolar Cell Tumor" of the Lung, Arch. P a t h . 4 1 : 175, 1946. 11. Ikeda, K . : Alveolar Cell Carcinoma of the Lung, Am. J . Clin. Path. 1 5 : 50, 1945.
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12. Kirklin, J . W., McDonald, J . E., Clagett, O. T., Moersch, H . J., and Gage, E . : Bronchogenio Carcinoma: Ceil Type and Other Eactors Eelating to Prognosis, Surg., Gynec. & Obst. 100: 429, 1955. 13. Liebow, A. A . : Tumors of Lower Eespiratory Tract, Atlas of Tumor Pathology. Sec tion V, Ease. 17, Armed Forces Institute of Pathology, 1952. 14. Malassez, L . : Examen histologique d'un cas de cancer encephaloide du poumon (epithelioma), Arch, de physiol. norm, et path., P a r . 3 : 353, 1876. 15. Mears, T. W., Kirklin, J . W., and Woolner, L. B . : The F a t e of Patients With Alveolar Cell Tumor of the Lungs, J . THORACIC SUEG. 27: 420, 1954.
16. Ochsner, A., Eay, C. J., and Acree, P . W . : Cancer of the Lung, Am. Eev. Tuberc. 70: 763, 1954. 17. Overholt, R. H., Meissner, W. A., and Delmonico, J . E . : Favorable Bronchiolar Car cinoma, Dis. Chest 2 7 : 403, 1955. 18. Overholt, E . H., and Bougas, J . A . : Factors in Lung Cancer Survivors, J . THORACIC SURG. 32: 508, 1956. 19. Paulson, P . L . : Survival Eates Following Eesection for Bronchogenic Carcinoma, Ann. Surg. 146: 997, 1957. 20. Simonds, J . P . , and Curtis, J . S.: Lesions Induced in the Lungs by the Intravenous In jection of Tar, Arch. Path. 19: 287, 1935. 21. Smith, L. W., and Gault, E . S.: Essentials of Pathology, Philadelphia, 1948, The Blakiston Company. 22. Spain, D. M.: The Association of Terminal Bronchiolar Carcinoma With Chronic Inter stitial Inflammation and Fibrosis of the Lungs, Am. Eev. Tuberc. 76: 559, 1957. 23. Storey, C. F . , Knudtson, K. P., and Lawrence, B . J . : Bronchiolar (Alveolar Cell) Car cinoma of the Lung, J . THORACIC SURG. 26: 331, 1953.
24. Watson, W. L., and Smith, E. E . : Terminal Bronchiolar or "Alveolar Cell" Cancer of the Lung. J . A. M. A. 147: 1-7, 1951. 25. Bell, J . W . : Discussion of Fitzpatrick et al.s 26. Barrett, E . J., Day, J . C , O'Eourke, P . V., Chapman, P . T., Sadeghi, H., Perry, R. W., and Tuttle. W. M.: Primary Carcinoma of the L u n g : Experience With 1,312 Pa tients, J . THORACIC & CARDIOVAS. SURG. 46: 292, 1963.
Colonel, MC, US Army, Alphonse
C. Gomez,
Major,
MC, US Army, Elmore M. Aronstam, Colonel, MC, US Army, and Arthur Steer, Colonel, MC, US Army, Denver,
Colo.
B
RONCHIOLAK carcinoma was initially described in the necropsy findings of a single case reported by Malassez14 in 1876. This observer was impressed by the fact that the major bronchi were free of tumor. Storey 23 credits Skorpil with the first report of bronchiolar carcinoma in a living patient; the tumor produced an undiagnosed shadow in an upper lobe resected in 1936. Since that time bronchiolar'carcinoma has been recognized with increasing frequency, and clinical experience with this tumor has reached a level of significance. It seems apropos, therefore, to question several of the dicta regarding bronchiolar car cinoma, which were derived solely from autopsy studies. Our experience, along with that of other observers, does not confirm a multicentricity of origin of bronchiolar carcinoma, and, further, we doubt that this tumor carries the same dismal prognosis as the more common pulmonary malignancies. Several points seem to merit consideration: review of the concepts of origin of bronchiolar carcinoma, the pathologic criteria essential for diagnosis, the relationship of this tumor to previous pulmonary disease, and, finally, examination of a documented clinical experience. THE ORIGIN OF BRONCHIOLAR CARCINOMA
The alveolar lining of the fetal lung disappears shortly after birth and this change is presumed to be functional, facilitating a more rapid interchange of gases between blood and alveolar air. The normal adult lung contains alveoli lined primarily by naked capillaries with only an occasional epithelial cell ap pearing in niches between the capillaries. There are certain pathologic circum stances under which the alveoli may become lined with epithelium; in each in stance the interalveolar septae develop a marked thickening. Such septal thick ening produces a relative immobilization of tissue, the number of capillaries is reduced and remaining capillaries are consequently displaced from the interface Prom the Thoracic Surgical Service and Department of Pathology, Fitzsimons General Hospital, Denver, Colo. Received for publication May 4, 1964. 614
Vol. 48, No. 4 October, 1964
BRONCHIOLAR CARCINOMA O F LUNG
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surface of the alveoli, and gaseous exchange within this altered area becomes unlikely. Such alveolar epithelization is evident in the chronic passive con gestion associated with aortic or mitral valve lesions, in chronic interstitial pneumonia, and in lipoid pneumonia. Diffuse epithelial hyperplasia along the alveolar septae can occur in man; in such instances the septae appear thickened as a result of simple piling of epithelial cell layers. Any chronic inflammatory process which initiates septal thickening by leukocytic infiltration may in turn be followed by fibrosis as the acute process subsides. Two experimental facts are of interest in regard to alveolar epithelization. Simonds and Curtis 20 noted marked alveolar epithelization about necrotic areas in the lungs following the intravenous injection of tar in heavy petrolatum into rabbits. Grady and Stewart 7 induced pulmonary tumors in strain A mice by the injection of 1:2::5:6 dibenzanthrene or methylcholanthrene; such tumors appeared after 5 weeks as a layer of cells lining alveoli. Thus, in the experi mental animal, alveolar epithelization can be produced with either benign or malignant characteristics. Two basic theories exist regarding the origin of the epithelial cells which line the alveoli in bronchiolar carcinoma. Ikeda, 11 Bell,3 and Delarue and Graham 5 were of the belief that the epithelial cells of bronchiolar carcinoma took their origin from normal alveolar epithelium. Acceptance of this theory is predicated on the belief that a normal alveolar epithelium exists in the human lung. Herbut's studies 10 have indicated that all primary carcinomas of the lung arise from the basal cells of the bronchial tree, and that either cuboidal or columnar cell types will spread along alveolar septae. Smith and Gault, 21 Storey, 23 and Liebow13 all believe that the cells which come to line the alveoli in bronchiolar carcinoma arise directly from the terminal bronchioles. In the light of accumulating clinical experience the latter theory appears more reason able. It is apparent that the early pathologic studies of bronchiolar carcinoma were carried out in patients who died with extensive pulmonary disease, and it was logical that the possibility of multicentric origin of such a tumor might be emphasized. The tumor is now recognized clinically, detected by cytologic study of sputum, and histologic study of resected specimens. Documentation of patient survivals over a period of years following treatment makes any multicentricity of origin unlikely. No doubt the enigmatic factor of host resistance is of great importance in determining whether or not a patient survives for a long period of time or develops a diffuse spread early in the course of the disease. The tumor exhibits a tendency to desquamate into alveolar spaces, thus bronchial embolization appears a likely mechanism of spread to either adjacent sites or the contralateral lung. Hawkins and associates,9 in a study of 12 Fitzsimons General Hospital pa tients treated by resection, found a total observation period of 79 years with tumor recurrence in only 2 of the patients. Storey's 23 statistical analysis of 205 cases from the files of the Armed Forces Institute of Pathology appears to sub stantiate a unicentric origin for bronchiolar carcinoma. Significant long-term
616
H E W L E T T E T AL.
J. Thoracic and Cardiovas. SurK.
survival rates as herein reported associated with lobectomy would not be pos sible in patients with tumors of multicentric origin. T H E PATHOLOGIC CRITERIA OF BRONCHIOLAR CARCINOMA
Gross.—Bronchiolar carcinoma may appear either as a discrete peripheral nodule of varied size or as a segmental or lobar consolidation resembling a localized pneumonic process in the state of gray hepatization. The nodular lesion may be well demarcated from the adjacent lung tissue or it may appear in an area of gross cicatrization. These nodules are soft to palpation in contradistinction to the rocklike hardness noted in association with other more common pulmonary malignancies. In those instances where the tumor involves an anatomic unit of the lung, the segment or lobe retains its normal contour in a consolidated state, the pleural surface is smooth, and lobular markings are prominent. The cut surface appears yellowish-brown in color. Necrosis and cavitation are rare, but mucus is frequently evident on the cut surface. Characteristically the larger bronchi do not reveal evidence of primary tumor; in the advanced pneumonic pattern there may be evidence of tumor extension along the course of major bronchi. Microscopic.—Typically bronchiolar carcinoma resembles adenocarcinoma, either bronchogenic or metastatic. It seems likely that many bronchiolar car cinomas have been mistakenly classified as adenocarcinomas without further study. Usually the initial pathologic report will suggest the possibility of the pulmonary lesion representing a metastasis from elsewhere in the body. Overholt's 17 re-evaluation of mucinous adenocarcinomas of the lung suggests that many bronchiolar carcinomas have been misclassified. The classic pattern is one of tall columnar cells growing along alveolar walls without disruption of the alveolar pattern. Such cells can be noted to arise in the peripheral bronchioles less than 0.1 cm. in diameter (Fig. 1). These tall columnar cells contain a finely granular cytoplasm with a vesicular nucleus located in the basal portion of the cell. Such cells may occur in a single layer or in multiple layers which give a sheetlike appearance. Cilia are uncommon (Fig. 2). It must be emphasized that the basic cell type—cuboidal, squamous, or anaplastic—may be poorly differentiated; in such cases an increased incidence of mitotic figures is noted (Fig. 3). Thickening of the alveolar septae will be noted as one proceeds from the margin toward the center of the tumor. The alveolar septae encroach on the alveolar space and fuse, producing an adenomatous pattern (Fig. 4). Papillary formation is frequent within alveolar spaces, and tumor cells may be noted lying free in alveolar spaces. Such desquamation accounts for positive bronchial washings in some patients and offers a possible source for bronchial embolization as a mechanism of tumor spread. A scirrhous, papillary, or adenomatous pattern of growth is often seen where bronchiolar carcinoma arises in an area of previous parenchymal inflammation (Fig. 5).
Vol. 48, No. 4 October, 1964
BEONCHIOLAR CARCINOMA OF LUNG
617
ft •?■"* ■ <& '.. *• ^
:,
-iy
^
V*
■
Fig. 1.—Bronchiolar carcinoma invading the mucosa of a medium-sized bronchus. Fig. 2.—Bronchiolar carcinoma. Cells growing on alveolar septae, alveoli distended with mucus.
The malignant cells may appear in lymphatics and blood vessels; the inci dence of these findings is not as frequent as is usually associated with the more common type of pulmonary malignancy. Marked lymphatic spread is associated with advanced disease and indicates a poor prognosis (Pig. 6). A varied cellular pattern may appear in bronchiolar carcinoma. Major bronchi are not invaded, although malignant cells may spread along their course. The tumor may remain localized to a single area for a long period. Its predilection for spread is intrapulmonary rather than via lymphatic channels.
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Direct extension to adjacent tissues is rare except in advanced terminal stages B W a t i a n of other possible sources of carcinoma is essential in estabUshlng the diagnosis of bronchiolar carcinoma. The histologie evidence of pre-existing chronic pulmonary inflammation is noted within the tumor site in more tnan 50 per cent of cases here reported. No correlation can be demonstrated between the histologie appearance of the tumor and the patient's survival.
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Fig. 5.- -Bronchiolar carcinoma arising in old cicatrix. Pig. 6.- -Perivascular lymphatic distribution of bronchiolar carcinoma. RELATIONSHIP TO PREVIOUS PULMONARY DISEASE
Bronchial obstruction is relatively frequent in association with squamous cell and anaplastic bronchogenic carcinoma; however, bronchial obstruction per se is rarely noted in association with bronchiolar carcinoma. Thus it cannot be assumed that the well-established parenchymal fibrosis frequently associated with bronchiolar carcinoma is the result of a pneumonitis secondary to bronchial obstruction. Beaver and colleagues,2 in a study of 121 cases of bronchiolar car-
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cinoma, found a positive history of previous pulmonary disease in 62 per cent. In the same study there was microscopic evidence of old inflammatory changes in 84 per cent of specimens. Spain 22 has reported the cases of 12 patients in whom the association of bronchiolar carcinoma with diffuse or focal fibrosis was marked. Auerbach 1 has observed that necropsy studies suggest that the general usage of antibacterial agents in the treatment of acute pulmonary inflammation contributes to a rising incidence of organization of pulmonary exudates. Conse quently small areas of parenchymal fibrosis appear as the sequelae of viral pneumonias. The frequent reporting of a relationship between bronchiolar car cinoma and interstitial inflammation or fibrosis cannot be ignored. Cuboidal epi thelial metaplasia occurs in a variety of pulmonary diseases as mentioned; such changes may result from a decreased respiratory function secondary to in flammatory thickening of the septae. Beaver 2 and Spain 22 have postulated that fibrosis and hyperplasia may alter the epithelium to render it more susceptible to specific carcinogens. The bronchiolar epithelial metaplasia secondary to fibrosing pneumonitis may well represent a precursor to bronchiolar carcinoma, with some degree of local hypoxia serving to trigger malignant changes in atypical epithelium. The pulmonary insult which precedes bronchiolar car cinoma need not be one pronounced in severity. It may range from repeated mild susceptibility to upper respiratory infection through the gamut of viral pneumonitis, pneumococcal pneumonia, and advanced tuberculosis. There ap pears to be good correlation between history and histologic findings of old pul monary inflammation. Random survey of pathologic reports from several hos pitals reveals fibrosis to be mentioned more frequently in relation to bronchiolar carcinoma than with the more common pulmonary malignancies. Our experi ence of significant history in 52 per cent, with positive histologic findings of previous pulmonary disease in 47 per cent, indicates that the relationship of bronchiolar carcinoma to parenchymal scarring is greater than could be at tributed to mere coincidence. CLINICAL
EXPERIENCE
Thirty-nine cases of bronchiolar carcinoma from five Army General hos pitals* have been studied. There appears to be no racial or sexual predilection for bronchiolar carcinoma. There were 24 males and 15 females in the group. Twenty-nine (74 per cent) were in the so-called cancer age group. Twenty-one (53 per cent) patients were hospitalized because of respiratory symptoms, and 18 (47 per cent) were hospitalized because of chance radiographic findings. History revealed 55 per cent to be smokers; of those with symptoms most ad mitted to chronicity with occasional periods of acute exacerbation. There is no specific symptom pattern which might be considered characteristic of bronchiolar carcinoma. Approximately 50 per cent admitted to a chronic cough of several years' duration, 9 patients presented with signs and symptoms of advanced pulmonary disease. A large volume of frothy sputum was not noted in any patient; mild hemoptysis occurred in only 5 patients. * F i t z s i m o n s , B r o o k e , W a l t e r Reed, L e t t e r m a n , a n d T r i p l e r h o s p i t a l s .
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"_,J-
Tlie physical findings were dependent upon the extent of the pulmonary pathologic condition and, being nonspecific, do not merit discussion. The roentgenographic findings associated with bronchiolar carcinoma are as protean as those attributable to pulmonary tuberculosis. A small peripheral opacity with either discrete or indefinite borders may represent a bronchiolar carcinoma. In 4 of the patients studied, a small isolated area of cavitation was evident on the routine posteroanterior films. Unilateral pleural effusion was the initial finding in 5 patients. The bilateral parenchymal infiltration or nodular pattern may simulate tuberculosis. Segmental or lobar pneumonic consolidation may lead to a tentative diagnosis of pneumonia or sequestration. The roent genographic findings recorded in the patients herein reported fall in the fol lowing categories: localized parenchymal infiltration, 47 per cent; solitary pul monary opacities, 27 per cent; bilateral parenchymal infiltrate or nodular dis ease, 16 per cent; and isolated cavitation, 10 per cent. In 5 patients the lesion was evident on roentgenograms for over one year; in 6 patients the lesion was observed for over 2 years; in one instance the lesion is documented on films over an 8-year period. Hawkins and associates,9 in a review of these several patients, noted some degree of enlargement of the lesion to be apparent in each progressive set of films. Such inadvertent roentgeno graphic documentation of a solitary pulmonary lesion affords the most accurate information in regard to the duration of disease and would tend to further discredit any theory of multicentric origin of bronchiolar carcinoma. TREATMENT AND PROGNOSIS
The classical report dealing with bronchiolar carcinoma is Storey's 23 sta tistical analysis of 205 cases which appeared in 1953. This study does much to clarify certain erroneous concepts which were established on the basis of necropsy examinations. Clinical patterns and radiographic variation were clearly presented. An attitude of hope is implied but the figures did not actually clarify the prognosis in patients treated for bronchiolar carcinoma. One hundred and fifty-five patients in the series underwent treatment; of these, 49, or 31.6 per cent, had thoracotomy, 10.2 per cent survived for 5 years after resection, while another 6.1 per cent were alive 3 years after resection. Both Overholt18 and Ochsner16 have stated that the survival rate in bronchogenic carcinoma appears to be well established within 2 years following therapy. Analysis of 39 cases of bronchiolar carcinoma treated in five U. S. Army General Hospitals has been carried out. Eleven patients (28 per cent) were not suitable for resection because of advanced disease. Diagnosis in this group was established by scalene node biopsy in 3, lung biopsy in 2, bronchial washings in 1, pleural fluid cell block in 1, and autopsy in 4. Symptomatic treatment com bined with irradiation did not delay the rapidly fatal course of the disease in these patients. Thirty patients (76 per cent) underwent exploratory thoracotomy. Of this group, 28 (81 per cent) were treated by resection, the following operations being utilized: 18 lobectomies, 5 segmentectomies, and 5 pneumonectomies.
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Lobectomy was the operation of choice except where the tumor appeared to cross an interlobar fissure. The operative mortality was 6.6 per cent. The 2 patients who died in the early postoperative period were subjected to resection despite obvious pleural spread of the disease. Thus 26 patients (92 per cent) survived over 1 year after resection. Twenty-three patients (82 per cent) have survived over 2 years (Table I ) . TABLE I. SURVIVAL : 26 PATIENTS—BRONCHIOLAR CARCINOMA TREATED BY EESECTION SURVIVAL (YR.)
NO. OF PATIENTS
1 +2 +3 +4 +5
3 5 4 5 _9_ 26
DEAD
-(2) -(3) 5
Twenty-three patients (82 per cent) of those treated by resection survived beyond the 2 year period which has been designated as that point which should predict longer survival in patients undergoing resection for bronchogenic car cinoma. Fitzpatrick 6 has recently reported a 2.5 year survival rate of 30 per cent in patients undergoing resection for bronchiolar carcinoma. Continued follow-up of our patients who survived beyond 2 years reveals that recurrence of the malignancy resulted in the death of 2 patients 3^2 years after resection; another 2 patients died of metastatic disease 6 years after resection. Thus the malignancy accounted for the eventual death of 17 per cent of those surviving beyond 2 years and suggests that a 2 year postoperative survival, clinically free of disease, does not necessarily indicate a cure. However, on the positive side of the ledger, 3 patients (13 per cent) of those who survived the 2 year period are still alive and well 10 years after resection. Tabulating figures from other published experiences along with those de rived from this study, one gains the impression that the results obtained from resection of bronchiolar carcinomas of the lung are definitely better than those associated with resection as treatment in the broad spectrum of bronchogenic malignancies (Table I I ) . TABLE NO. OP PATIENTS
AUTHOR
EXPLORED
Bronchiolar "Watsonz* Fitzpatricke Bellas U. 8. Army Barrett^
1951 1961 1961 1963 1963
33 33 21 39 31
BurforcL*
1958
1,008
II
(%)
Carcinoma 48.0 60.6 76.0 74.0
Bronchogenic Carcinoma 60.0
RESECTED
SURVIVALS
(%)
(%)
2+YR.
5 YR.
87 65 57 93 64.5
43 30 25 82
33.0
35
38
8.3 32.0 40 22.0
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Burford's report dealing with the broad spectrum. of bronchogenic car cinoma noted that 5 per cent of the patients who survived 5 years were treated for bronchiolar carcinoma. This would suggest that survival in patients with bronchiolar carcinoma exceeds that associated with other bronchogenic car cinomas. SUMMARY
Numerous clinical reports have now documented the bizarre histologic pat terns of bronchiolar carcinoma and its relationship to old pulmonary fibrosis. The radiographic patterns associated with this particular malignancy are as varied as those encountered in pulmonary tuberculosis. A high rate of resectability, even after several years of radiographic observation, suggests that this tumor tends to be localized and slow in growth. Relatively long survivals fol lowing lobectomy and long periods of x-ray observation of a questionable pul monary shadow which is eventually proved to be bronchiolar carcinoma serve as proof of the unieentricity of origin of the tumor. The inadvertent radiographic recording of the presence of these tumors over a period of years in the same patient confirms the tendency of this malignancy to remain localized for a long period. Considering the continued dismal prognosis associated with the broad spec trum of bronchogenic carcinoma, the continued reporting of experiences with bronchiolar carcinoma seems justified. This experience appears to lend credence to the rationale of an extremely aggressive surgical approach in the management of the undiagnosed pulmonary nodule or infiltrate.
REFERENCES 1. Auerbaoh, 8. H., Mims, O. M., and Goodpasture, E . W . : Pulmonary Fibrosis Secondary to Pneumonia, Am. J . Path. 28: 69, 1952. 2. Beaver, O. L., and Shapiro, J . L . : A Consideration of Chronic Pulmonary Parenchymal Inflammation and Alveolar Cell Carcinoma With Regard to a Possible Etiologie Relationship, Am. J . Med. 2 1 : 879, 1956. 3. Bell, E . T . : Hyperplasia of the Pulmonary Alveolar Epithelium in Disease, Am. J . P a t h . 19: 901, 1943. 4. Burford, T. H., Center, S., Ferguson, T. B., and Spjut, H . J . : Results in the Treatment of Bronchogenic Carcinoma, J . THORACIC SURG. 36: 316, 1958.
5. Delarue, N . C , and Graham, E . A . : Alveolar Cell Carcinoma of t h e Lung (Pulmonary Adenomatosis, Jaagsiekte?) : A Multicentric Tumor of Epithelial Origin, J . THORACIC SURG. 18: 237, 1949.
6. Fitzpatrick, H . F . , Miller, R. E., Edgar, M. S., J r . , and Begg, C. F . : Bronchiolar Car cinoma of t h e Lung, J . THORACIC & CARDIOVAS. SURG. 4 2 : 310, 1961.
7. Grady, H . G., a n d Stewart, H . L . : The Histogenesis of Induced Pulmonary Tumors in Strain A Mice, Am. J . Path. 16: 417, 1940. 8. Geever, E . F . , Neubuerger, K. T., and Davis, C. L . : The Pulmonary Alveolar Lining Under Various Pathologic Conditions in Man and Animals, Am. J . P a t h . 19: 913, 1943. 9. Hawkins, J . A., Hansen, J . E., and Howbert, J . : A Clinical Study of Bronchiolar Car cinoma: A Clue t o Unieentricity or Multicentrieity, Tr. of the 21st Research Con ference on Pulmonary Diseases, VA-Armed Forces, 1962, p . 143. 10. Herbut, P . A . : Bronchiolar Origin of "Alveolar Cell Tumor" of the Lung, Arch. P a t h . 4 1 : 175, 1946. 11. Ikeda, K . : Alveolar Cell Carcinoma of the Lung, Am. J . Clin. Path. 1 5 : 50, 1945.
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12. Kirklin, J . W., McDonald, J . E., Clagett, O. T., Moersch, H . J., and Gage, E . : Bronchogenio Carcinoma: Ceil Type and Other Eactors Eelating to Prognosis, Surg., Gynec. & Obst. 100: 429, 1955. 13. Liebow, A. A . : Tumors of Lower Eespiratory Tract, Atlas of Tumor Pathology. Sec tion V, Ease. 17, Armed Forces Institute of Pathology, 1952. 14. Malassez, L . : Examen histologique d'un cas de cancer encephaloide du poumon (epithelioma), Arch, de physiol. norm, et path., P a r . 3 : 353, 1876. 15. Mears, T. W., Kirklin, J . W., and Woolner, L. B . : The F a t e of Patients With Alveolar Cell Tumor of the Lungs, J . THORACIC SUEG. 27: 420, 1954.
16. Ochsner, A., Eay, C. J., and Acree, P . W . : Cancer of the Lung, Am. Eev. Tuberc. 70: 763, 1954. 17. Overholt, R. H., Meissner, W. A., and Delmonico, J . E . : Favorable Bronchiolar Car cinoma, Dis. Chest 2 7 : 403, 1955. 18. Overholt, E . H., and Bougas, J . A . : Factors in Lung Cancer Survivors, J . THORACIC SURG. 32: 508, 1956. 19. Paulson, P . L . : Survival Eates Following Eesection for Bronchogenic Carcinoma, Ann. Surg. 146: 997, 1957. 20. Simonds, J . P . , and Curtis, J . S.: Lesions Induced in the Lungs by the Intravenous In jection of Tar, Arch. Path. 19: 287, 1935. 21. Smith, L. W., and Gault, E . S.: Essentials of Pathology, Philadelphia, 1948, The Blakiston Company. 22. Spain, D. M.: The Association of Terminal Bronchiolar Carcinoma With Chronic Inter stitial Inflammation and Fibrosis of the Lungs, Am. Eev. Tuberc. 76: 559, 1957. 23. Storey, C. F . , Knudtson, K. P., and Lawrence, B . J . : Bronchiolar (Alveolar Cell) Car cinoma of the Lung, J . THORACIC SURG. 26: 331, 1953.
24. Watson, W. L., and Smith, E. E . : Terminal Bronchiolar or "Alveolar Cell" Cancer of the Lung. J . A. M. A. 147: 1-7, 1951. 25. Bell, J . W . : Discussion of Fitzpatrick et al.s 26. Barrett, E . J., Day, J . C , O'Eourke, P . V., Chapman, P . T., Sadeghi, H., Perry, R. W., and Tuttle. W. M.: Primary Carcinoma of the L u n g : Experience With 1,312 Pa tients, J . THORACIC & CARDIOVAS. SURG. 46: 292, 1963.